Medicinal plant Cyperus rotundus holds promise for new COVID-19 therapies

COVID-19 (coronavirus disease 2019) is a viral respiratory illness that is spreading around the world. It has been declared a public health emergency and pandemic by the World Health Organization (WHO). A lack of effective therapeutic efforts has hampered treatment for COVID-19.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Main Protease (M^PRO) plays an essential role in the viral replication cycle.

Once inside a host cell, SARS-CoV-2 begins to produce non-structural proteins that facilitate replication and propagation, among which is the major protease 3-chymotrypsin-like protease (M^PRO), responsible for the proteolytic treatment.

This enzyme demonstrates extreme specificity towards viral polypeptide sequences, interacting minimally with host proteins. This means that any drug targeting the enzyme is unlikely to also inhibit host proteases, making the essential SARS-CoV-2 enzyme a particularly attractive drug target.

Cyperus rotundu is a plant with a history as herbal medicine, containing many chemicals frequently found to be medicinal in nature: flavonoids, terpenoids, etc. Compounds from the plant have demonstrated some inhibitory activity against HIV by modulating the enzyme CYP3A4, and therefore in a drug discovery effort, Kumar et al. (July 2021) computer screened these natural compounds against M^PRO in an article recently published at Computers in biology and medicine.

Ligand screening

A library of 390 compounds from Cyperus rotundu has been assembled in silico and checked for drug resemblance, having good bioavailability by the ability to cross membranes, leaving 354 relevant ligands.

7,938 conformers were generated from these ligands, and docking simulations were performed against M^PRO, based on the crystal structure of the enzyme. The top 30 compounds ranked in terms of the LibDock score, which provides a numerical value based on electrostatic interactions between molecules, have been carried forward for more detailed binding energy testing. Compounds that have bound to M^PRO active site with negative binding energy, and therefore providing a suitable stable binding to an inhibitory drug, were selected from the drug tracks, leaving 12 compounds of interest.

Lupeol demonstrated the most favorable docking affinity towards M^PRO, followed by β-amyrin acetate, achieving scores of -70.03 and -59.33 kcal / mol, respectively. Interestingly, the antiretroviral protease inhibitor drugs lopinavir and ritonavir, which have been shown to be effective against COVID-19 in some studies, achieved scores of only -50.25 and -68.58 kcal / mol, respectively. . Other compounds have shown good binding affinities with M^PRO, comparable to these commercial drugs, and were therefore also selected for further consideration: leanolic acid, -amyrin, stigmasta-5,22-dien-3-ol and valrenyl acetate. The root mean square deviation of the ligands once bound was also evaluated to determine the flexibility of the compounds, α-amyrin, stigmasta-5,22-dien-3-ol and valrenyl acetate demonstrating the greatest rigidity. Beta-amyrin followed by stigmasta-5,22-dien-3-ol had the greatest total binding free energy, indicating stronger intermolecular interactions and more stable bonds.

Bioavailability and toxicity

Beta-amyrin and stigmasta-5,22-dien-3-ol were examined for pharmacokinetics and toxicity, both demonstrating adequate oral bioavailability and exceptional intestinal absorption approaching 100%. They also strongly test the blood-brain barrier and central nervous system permeability, suggesting that they would biodistribute well through both. The drugs do not inhibit human cytochrome P450, indicating that they are not metabolized.

The drug tracks were exposed to the Ames toxicity test, exhibiting low toxicity, although they obtained relatively high scores in terms of acute toxicity taking into account the LD50 values ​​for the rat and the minnow for them. compounds. The group suggests that both drug tracks are likely to be well tolerated by humans, although this needs to be verified experimentally by in vitro and in vivo studies.

The researchers concluded that Cyperus rotundu Linn. herbal medicine helps treat viral infections in the traditional way, and may be useful in the development of new and effective therapies against COVID-19.